1. Introduction

The prevalence of adenomyosis fluctuates between 5 and 70% ^[1]. Before the age of 40 years, the disease affects 2 in 10 women, whereas between 40 and 50 years, the incidence increases to 8 in 10 women ^[2]. However, the incidence of adenomyosis is difficult to establish due to the lack of a unified definition and diagnostic criteria based on noninvasive diagnostic tests ^[3]. There are no pathognomonic clinical features for adenomyosis, nor laparoscopic criteria that could be implemented for the diagnosis ^[4]. Nevertheless common known fact is that it is estrogen dependent disease and if hormonal treatment fails, hysterectomy is an option in definitive treatment.

In fact, adenomyosis was previously diagnosed in premenopausal women only on the basis of pathological examination after hysterectomy ^[5][6]. Nowadays, the diagnosis is based on imaging techniques such as transvaginal ultrasound scan (US) and magnetic resonance imaging (MRI) ^[7]. In one third of cases, adenomyosis is asymptomatic. The most common clinical symptoms are menorrhagia (up to 50% of patients), dysmenorrhea (30%) and metrorrhagia (20%), with other medical conditions such as enlarged uterus and infertility ^[2][6].

Adenomyosis may be accompanied by other mild oestrogen-dependent benign disorders such as endometriosis (70%), uterine fibroids (50%) and endometrial hyperplasia (35%). In the retrospective analysis of 945 patients who underwent hysterectomy, a significant positive correlation was found between the progression of adenomyosis and history of prior abortion, history of previous pregnancies and occurrence of leiomyoma. By contrast, there was no correlation with smoking, normal delivery, caesarean section, endometrial hyperplasia or ovarian endometriosis ^[8].

2. Biological Influence of Adenomyosis on Fertility—Possible Mechanisms

Recent studies show that adenomyosis negatively affects in vitro fertilisation, pregnancy and the live birth rate, as well as increases the risk of miscarriage. In addition, adenomyosis enhances the risk of obstetric complications, such as premature birth and preterm rupture of the amniotic membranes ^[9][10].

Fertility in adenomyotic patients could be disturbed by various mechanisms. Abnormal utero-tubal gamete and the embryo transport and disruption of endometrial function and receptivity have been described ^[2]. An enlarged uterus, anatomical distortion and intramural adenomyoma can all influence the shape of the uterine cavity. It may have a negative impact on sperm migration, embryo transfer and implantation potential ^[2][11]. The researchers suggested an association between spontaneous abortion and JZ function ^[12]. Chiang at al. observed a comparable dependence ^[13]. An average JZ greater than 7 mm was correlated with higher implantation failure ^[14].

Hyperactivity of the myometrium is also observed in adenomyosis. Changes in myocytes are also found on the cellular level—calcium circulation is distorted, which implies irregular muscle contractions, dysfunctional uterine hyperperistalsis with increased intrauterine pressure and the development of hyperplastic myometrial tissue. The thickening of the junctional zone is a visible sign of endometrial invasion into the myometrium. Alerted myometrial contractility may impair sperm progression towards the peritoneal opening of the tubes ^[2].

Distortion of the uterine cavity can be visualised in hysterosalpingography (HSG), and occurs in 78% of patients with diffuse adenomyosis and 54% cases of focal adenomyosis compared to 37% of women without adenomyosis. These findings may suggest the association between adenomyosis and the probability of abnormal utero-tubal transport ^[5].

Adenomyosis-associated changes may also worsen endometrial receptivity ^[15]. Endometrial receptivity is defined as physiological molecular and histological phenomena occurring during a restricted time of the menstrual cycle, making the uterus exclusively receptive to blastocyst attachment and implantation (so-called implantation window).

Evidence of reduced endometrial receptivity and impaired decidualisation in adenomyosis was found at the molecular level. Abnormal function of the implantation-associated molecules such as HOXA10, LIF, MMP, IL-6, IL -10, cytochrome P450 and RCAS1 has been described ^[16].

The decreased expression level of HOXA10 genes in the secretory phase endometrium appears to be involved in impaired implantation in women with adenomyosis. Similarly, a deregulation of leukaemia inhibitory factors (LIF) in uterine flushing fluid during the implantation window has been reported in adenomyosis ^[5][17][18]. Jiang et al. reported the down-regulation of the NR4A receptor and FOXO1A in adenomyotic tissue, which leads to incorrect decidualisation ^[19]. Whether these changes can be restored by the progestins given during the implantation window remains unknown due to the lack of conclusive data in humans ^[20][21].

Certain cell adhesion molecules, such as integrins, are also extensively studied in adenomyosis. Integrins are transmembrane receptors, which activate signalling pathways and mediate cellular signals such as regulation of the cell cycle. Integrins are responsible for endometrial receptivity. Abnormal expression of both integrin β-3 and OPN mRNA (osteopontin, responsible for the trophoblast-endometrium interaction) is found in adenomyosis patients, and it is suggested that this abnormal expression may be responsible for in vitro fertilisation (IVF) failure despite good embryo quality ^[22]. Integirn β3 together with osteopontin (OPN) are involved in cell–cell interactions, and their proper functioning is inevitably related to uterine receptivity. In the endometrium of adenomyotic patients, the levels of β3 and OPN were statistically lower compared to nonadenomyotic controls ^[16][18]. The influence of medical treatment (gonadotrophin-releasing hormone (GnRH) analogues, ovarian stimulation) on integrin expression and endometrial receptivity has so far been studied in animal models and could only partially be conclusive for human pathology ^[23][24].

It is a well-known fact that chronic inflammation has a negative impact on fertility ^{[25][26][27][28][29]}. In the case of a patient with adenomyosis, an increased expression of IL-1b and CRH (corticotrophin-releasing hormone) in the eutopic endometrium was observed ^[25]. In addition, the presented data showed differences in both cellular and humoral immunity in the eutopic endometrium of an adenomyotic uterus compared to the unaffected control ^[26]. Ishikawa et al. reported an increased inflammatory response in the endometrium due to the presence of a higher expression of pro- and anti-oxidative cytokines like Cu, Zn-SOD and Mn-SOD ^[27]. Other authors confirmed these findings by investigating the nitric oxide (NO) concentration in endometrium, macrophage activation, Il-6 and neurotrophins ^[16][28]. NO is involved in modulating uterine contractility during pregnancy and relaxing vascular smooth muscles. An abnormal high level of free radicals such as nitric oxide has a negative impact on sperm transport, implantation and decidualisation ^[29].

3. Conclusions

There is no specific treatment for patients with adenomyosis who want to retain their uterus or wish to preserve fertility ^[30]. Sometimes, combined treatment can be proposed: Laparoscopy, GnRH treatment and in vitro fertilisation ^[31]. Women who did not want to preserve fertility can be treated with pharmacological or definitive surgical methods. To pharmacological methods counts: NSAID (non-steroids anti-inflammatory drugs), oral contraception given periodically or continuous, without bleedings breaks, progestins, GnRH analogues and SPRM drugs (selecite progesteron receptors modulators - actually in clinical trials). Definitive surgical treatments has already been mentioned and can only be achieved by hysterectomy.

In fertility preservation uterus should be retained and only adenomyosis foci should be resected. When comparing pharmacological and surgical treatment, the latter appears to be more effective but some details are unclear, i.e., how long pregnancy should be delayed after treatment and whether hormone treatment after surgery improves fertility outcome. Despite many studies on the pathogenesis of fertility failure in adenomyosis, their results are not correlated with treatment. Thus, it is of great importance to explore new, more effective, safe and less invasive managing strategies in women with infertility due to adenomyosis.